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EnglishThe role of p53 as a prognosticmarker in head and neck squamous cellcarcinoma (HNSCC) is controversial. The intentof this study was to evaluate rigorously theprognostic value of p53 genetic status. Methods: Tumor samples from 480 HNSCC patients treated surgically with curative intent were collected in a prospective multicenter study over 5 years. 57 cases were not analyzed due to technical or administrative factors. Mutation status was determined in the 423 remaining cases, using p53 chip (GP53 GeneChip from Affymetrix, Inc., Santa Clara, CA) which identifies mutations in exons 2 through 11. Indeterminate calls were investigated using Surveyor and/or DHPLC analysis and all mutations were confirmed with an automated fluorescent system or manual sequencing. Clinical follow-up was accomplished following Eastern Cooperative Oncology Group protocol. Results: Median follow-up of the 423 evaluable subjects was 5.4 years with all patients followed at least 3 years. Mutation of p53 gene was present in 224 (53%) cases. There we significantly fewer mutations in tumors arising in the oropharynx (chi-square p = 0.02). The presence of p53 mutation was significantly associated with decreased overall survival. Median survival for patients with tumors with p53 mutation was 3.1 years compared to 5.4 years fro WT tumors (HR = 1.4, 95% CI =1.1 to 1.8, p = 0.01 log-rank test). This proved to be independent of tumor site in multivariate analysis. When mutations were segregated according to their effect on biological function through alteration of key DNA binding domains a Cox regression analysis revealed a statistically significant linear effect of the more disruptive mutations on overall survival with a HR of 1.3 for comparison of each group to the one of lower risk (more vs. less disruptive mutation v. WT (p = 0.001 Wald test). Conclusions: This large prospective series shows a strong relationship between TP53 mutation and prognosis in HNSCC patients. Furthermore, the biological impact of specific mutations has a predictable graded relation to clinical outcome. The results set the stage for use of p53 genetic status in the design of future clinical trials and support the development of targeted therapy to restore wild-type p53 function.
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| Titolo: | Prognostic implication of p53 mutations in HNSCC: Results of Intragroup margin study |
| Autori: | |
| Data di pubblicazione: | 2006 |
| Rivista: | |
| Abstract: | The role of p53 as a prognosticmarker in head and neck squamous cellcarcinoma (HNSCC) is controversial. The intentof this study was to evaluate rigorously theprognostic value of p53 genetic status. Methods: Tumor samples from 480 HNSCC patients treated surgically with curative intent were collected in a prospective multicenter study over 5 years. 57 cases were not analyzed due to technical or administrative factors. Mutation status was determined in the 423 remaining cases, using p53 chip (GP53 GeneChip from Affymetrix, Inc., Santa Clara, CA) which identifies mutations in exons 2 through 11. Indeterminate calls were investigated using Surveyor and/or DHPLC analysis and all mutations were confirmed with an automated fluorescent system or manual sequencing. Clinical follow-up was accomplished following Eastern Cooperative Oncology Group protocol. Results: Median follow-up of the 423 evaluable subjects was 5.4 years with all patients followed at least 3 years. Mutation of p53 gene was present in 224 (53%) cases. There we significantly fewer mutations in tumors arising in the oropharynx (chi-square p = 0.02). The presence of p53 mutation was significantly associated with decreased overall survival. Median survival for patients with tumors with p53 mutation was 3.1 years compared to 5.4 years fro WT tumors (HR = 1.4, 95% CI =1.1 to 1.8, p = 0.01 log-rank test). This proved to be independent of tumor site in multivariate analysis. When mutations were segregated according to their effect on biological function through alteration of key DNA binding domains a Cox regression analysis revealed a statistically significant linear effect of the more disruptive mutations on overall survival with a HR of 1.3 for comparison of each group to the one of lower risk (more vs. less disruptive mutation v. WT (p = 0.001 Wald test). Conclusions: This large prospective series shows a strong relationship between TP53 mutation and prognosis in HNSCC patients. Furthermore, the biological impact of specific mutations has a predictable graded relation to clinical outcome. The results set the stage for use of p53 genetic status in the design of future clinical trials and support the development of targeted therapy to restore wild-type p53 function. |
| Handle: | http://hdl.handle.net/11586/62574 |
| Appare nelle tipologie: | 1.5 Abstract in rivista |
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